Abstract
Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1α (HIF1α). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic-ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo.
Highlights
Ischemic heart disease, stroke and cancer are associated with cellular hypoxia and nutrient/glucose deprivation [1,2,3,4]
To determine whether Hypoxia-inducible gene domain 1A (HIGD1A) expression and induction is regulated by Hypoxia-inducible Factor-1a (HIF1a) or HIF2a, we used Hypoxia Inducible Factor (HIF)-deficient mouse embryonic fibroblasts (MEFs) and trophoblast stem cells (TSCs)
We have demonstrated the stress dependent nuclear localization of the HIF-1 target mitochondrial protein HIGD1A in vitro and in vivo
Summary
Stroke and cancer are associated with cellular hypoxia and nutrient/glucose deprivation [1,2,3,4]. The Hypoxia Inducible Factor (HIF) family of transcriptional regulators modulates the survival of cells in response to these stressors [5] [6,7,8]. HIFs are heterodimers consisting of oxygen sensitive, labile a subunits complexed with stable b subunits. With increasing levels of oxygen, HIF-a subunits are hydroxylated at conserved proline residues, mediated by a family of prolyl-4hydroxylase domain (PHD) enzymes. Hydroxylated HIFa is recognized and targeted for proteasomal degradation by the von Hippel-Lindau protein (pVHL) complex. PHD activity ceases and the rate of hydroxylation declines leading to HIF-a accumulation [9,10,11]. HIF-1a heterodimerizes with HIF-1b, and regulates the expression of scores of adaptive/survival genes. Therapeutic manipulation of HIF-hydroxylases has obvious appeal [12]
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